HPV-16

Humanpapilloma virus (HPV) is now the leading cause of certain types of throat cancer. Dr. Michael Moore, director of head and neck surgery at UC Davis and an HPV-related cancer expert, answers some tough questions about the trend and what can be done about it.

Q: What is HPV and how is it related to head and neck cancers?

A: There are about 150 different types of HPV, but HPV 16 is the one that most frequently causes cancers that affect the tissue in the oropharynx, which includes back of the throat, soft palate, tonsils and the back or base of the tongue. You can get non-cancerous lesions from other types of HPV that look like warts in the nose, mouth or throat, called papillomas. Some can develop in childhood just from exposure early in life. Some develop later in life and only occasionally turn into cancer.

Q: How do you get HPV?

A: HPV can spread from mother to her baby around the time of delivery. It also spreads through unprotected vaginal, anal or oral sex, and even open-mouth kissing. Some people have been found to be infected without an obvious cause.

Q: How does HPV cause cancer?

A: Most people who are infected clear the virus on their own. In a small group of people it hangs around and causes a persistent infection. Around 1% of US adults have a persistent HPV 16 infection, and in a small subset of these individuals the DNA of the virus incorporates itself into the DNA of the person infected and can start to make proteins that then predispose that person to developing cancer.

Q: How prevalent are HPV-related throat cancers?

A: Traditionally, the risk factors for head and neck cancers were tobacco and alcohol use, but over the last 20 or 30 years we found the rates of those cancers going down because smoking rates have gone down. Meanwhile, the incidence of head and neck cancers related to HPV has gone up more than 200 percent over this time period. This increase has been so dramatic that HPV-related throat cancer has recently surpassed cervical cancer as the most common HPV-related cancer in the United States.

Q: Why are the rates going up?

A: Unlike with cervical cancer, in which the PAP smear is highly effective at finding potentially cancerous or pre-cancerous cells, there is no good screening test for these head and neck cancers. Currently, the use of swab tests for HPV is effective in finding out if you have an HPV infection, but not in determining if the infection will be persistent or if you will ever develop cancer. As a result, such tests are not endorsed as a way to screen for these tumors.

Q: Do both men and women get thee cancers?

A: Men are four times more likely to be diagnosed with an HPV-related head and neck cancer. Researchers don’t yet know why. It may have to do with sexual practices or related to the types of exposure they receive. The local or systemic immune system may also play a role.

Q: Can HPV-related head and neck cancers be prevented?

A: We have a very effective vaccine against HPV, and we know the vaccine can prevent oral HPV infections. In fact, studies have shown that the vaccine is 93 percent effective in preventing the oral infections that cause head and neck cancers. We recommend two injections for adolescents under age 15 and three for those over 15. The vaccine is recommended for children age 10-11, but vaccination can start in children as young as age 9, and in boys as late as age 21 and in girls as late as 26. It is also important to maintain safe sexual practices and avoid other potentially cancer-causing exposures such as tobacco, alcohol and marijuana.

Q: What are the main barriers to vaccination?

A: Studies have shown that the biggest reason kids don’t get it is lack of physician endorsement or recommendation. The American Cancer Society is trying to change that, asking physicians to introduce it to parents when they discuss other adolescent vaccines. There has also been concern that parents aren’t comfortable talking about sexuality with their children, and some have worried that if the child gets the vaccine they are more likely to be sexually active. That theory has been debunked in scientific studies.

Q: How safe and effective is the HPV vaccine?

A: It has a very safe track record and is continually undergoing evaluation to look for potential side effects. While there are some risks with any vaccine, one of the most common side effects is that patients may feel light headed after being vaccinated, and it is recommended they are observed for 15 minutes afterward.

When actor Michael Douglas told a reporter that his throat cancer was caused by HPV contracted through oral sex, two themes emerged that had nothing to do with celebrity gossip. The first was incredulity — since when was oral sex related to throat cancer? Even the reporter thought he had misheard. The second was embarrassment. This was too much information, not only about sexual behavior but also about one’s partners.

Douglas apologized, and maybe the world was not ready to hear the greater truth behind what he was suggesting.

That was four years ago.

Today, there is no doubt in the medical community that the increase in HPV-related cancers such as the one Douglas described — which he later explained was found at the base of his tongue — is caused by sexual practices, in his case cunnilingus. And there is an urgency to better treat and prevent what is becoming the one type of oral cancer whose numbers are climbing, especially among men in the prime of their lives who have decades to live with the consequences of their cancer treatment.

The number of people diagnosed with HPV-related oropharyngeal cancer, tumors found in the middle of the pharynx or throat including the back of the tongue, soft palate, sides of throat and tonsils — is relatively small — about 12,638 men and 3,100 women in the United States each year, according to the Centers for Disease Control and Prevention. But these numbers are expected to continue to rise, overtaking incidence of cervical cancer by 2020. One study revealed the presence of HPV in 20.9 percent of oropharyngeal tumors before 1990, compared with 65.4 percent in those sampled after 2000.

Alarming trend
It’s an alarming trend considering HPV, or human papilloma­virus, is the most common sexually transmitted infection in the country. The CDC estimates that nearly all sexually active men and women will get a form of the virus at some point. Although most HPV infections go away on their own, they are causing 30,700 cancers in men and women every year, including cervical, vaginal and penile cancers along with oral cancers.

Health agencies are pushing hard for HPV vaccinations, which they say could prevent most of those cancers. The CDC says all 11- and 12-year-olds should be ­vaccinated. And last year, the Food and Drug Administration approved a new two-dose series for children ages 9 to 14. And the American Academy of Pediatrics recently updated its vaccine recommendations to reflect that two-dose schedule, a reduction from the three shots previously required. (Children over 14 still need three shots.) The hope is to increase rates of completed vaccinations, which have lagged in the decade since the vaccines were released, averaging 42 percent for girls and 28 percent for boys, far below the Healthy People 2020 goal of 80­ percent.

The patients showing up in Ben Roman’s office at Memorial Sloan Kettering Cancer Center in New York, where he works as a head and neck surgeon and ­health-services researcher, came of age not only before these vaccines hit the market, but also before HPV and its link to cancers was fully understood. These cases, experts say, probably reflect several separate but interconnected factors: the sexual revolutions of the 1920s and 1960s that introduced more HPV into the general population, the changing sexual practices of young people who report more histories of oral sex, and that it can take 10 to 30 years for tumors to develop after an infection.

Roman has seen an increase in a new type of head and neck cancer patient. They are typically white, middle-aged men, ­otherwise healthy, who have no history of smoking or drinking. They may have first noticed a mass in their necks or lymph nodes while buttoning a shirt or shaving. An ear, nose and throat doctor has determined the primary source of the cancer: the tonsils or base of the tongue.

“Most people are familiar with tonsils in the back of the throat,” Maura Gillison, a leading expert in HPV-related cancers at the ­University of Texas MD Anderson Cancer Center, said. “But we also have them in the base of the tongue.”

The palatine tonsils are on the sides of the throat, and there are also lingual tonsils on the back of the tongue. Both areas are made of the same lymphoid tissue at particular risk for HPV infection, and are part of what specialists call Waldeyer’s Ring.

Experts are not sure why an HPV infection in the tonsils is more likely to lead to cancer. It could be because of their anatomy, which has crypts and crevices, making it harder to clear an infection. Gillison said it could also be because of where the tonsils are in the body, an area that serves as a transition from the outside to the inside, much like the genital tract and cervix.

German researcher Harald zur Hausen identified the types of HPV that cause cervical cancer 34 years ago, work that earned him the Nobel Prize in 2008 and contributed to the development of the HPV vaccine. One of those types, HPV-16, is identified in more than half of cancers in the oropharynx, according to the National Cancer Institute.

But there are important distinctions between men and women when it comes to HPV-related cancers. Cervical cancer deaths, for example, have been greatly reduced through early detection with the use of Pap smears. The same screening for precursor lesions or pre-cancer is not yet possible for the oropharyngeal cancers, commonly referred to as OPC or OSCC, for oropharyngeal squamous cell carcinomas.

The male risk
Another difference is how men and women respond to infection. The majority of women develop antibodies to clear HPV when exposed vaginally. These antibodies remain in the body so that a woman is protected from a subsequent oral infection. Men, in contrast, are much less likely to develop antibodies after genital exposure to the virus. When tested, their titers — a measurement of antibodies — are lower, leaving them five times more likely than women to have an oral infection.

HPV is considered an unusual virus because it does not travel through the bloodstream. Infection is localized, meaning it stays at the place where contact occurs. In tonsil cancer, then, oral sex becomes a relevant risk factor, so significant that in an article in the Journal of Clinical Oncology, Gillison and her colleagues stated that the number of these oral sex partners in a lifetime is the behavior measure that is, “. . . most strongly, consistently, and specifically associated with OPC (tonsil and base of tongue).”

Treating a cancer related to a sexually transmitted infection brings up sensitive questions. Roman said a patient’s spouse will often pull him aside to ask: “When did he get this? Was he cheating?” He suggests the patient was probably exposed years ago. But from the viewpoint of prognosis, the HPV-related cancers respond better to treatment.

That fact has prompted rapid changes in treatment protocols that were as recently as five years ago based on heavy smoking and drinking. These new strategies back down from the aggressive radiation, chemotherapy and surgery that exposed patients to high toxicity and could damage the ability to speak and swallow.

When Gillison started her research in 2000, there was little awareness that sexual behavior contributed to cancer of the throat, and fellow researchers were skeptical.

“People were laughing. They thought it was absurd,” she said. Now, Gillison is credited with formally putting together the behavioral data and biomarkers to quell any skepticism, Carole Fakhry, an associate professor of otolaryngology and surgeon at Johns ­Hopkins, said.

Others had noted HPV in oral cavity cancer, but no one was sure whether it was a fluke or more significant. So Gillison reviewed tumor specimens collected by a colleague and then set out to study all of the available ­literature, presenting an analysis in 2009 that compared the ­survival rates of those with HPV-positive and -negative oropharynx cancers. Gillison describes her work — a confluence of observations in the lab and clinic — as an act of serendipity.

“I have always been interested in the association between ­infectious diseases and tumors because there are so many ­opportunities to intervene. If an infection causes a cancer, you can try to prevent infection in the first place, or screen, or if it’s developed you can use the fact that it’s associated with a virus — you can treat cancer by treating infection.”

As far as vaccination’s effect on preventing OPC in men, data is still under review. Officially, the vaccine is recommended for boys and young men to prevent genital warts and anal pre-cancers. But those focused on pediatrics, such as Margaret Stager, director of adolescent medicine at MetroHealth medical center in Ohio and an official spokeswoman for the American Academy of Pediatrics, say that HPV vaccination clearly decreases spreading of HPV through the community, offering immediate, midrange and long-term benefits. And the current vaccines do protect against HPV-16, one of the high-risk types of the virus found in both cervical cancer and a majority of OPC.

New, easier vaccine
The new two-dose vaccination is designed to reach children when their antibody response is highest and make completion less cumbersome, as are electronic medical records that cue physicians when a vaccine is due. The District of Columbia is one of the few areas that has made the vaccine a required immunization for students in grades six through 12, although families may opt out.

There is still a gap in knowledge among some general ­practitioners and dentists, according to Gillison.

It is not uncommon for her to hear a story from a patient who comes to her after six months or so after going to his doctor.

“He told me not to worry ­because I was fighting off an infection. He gave me antibiotics. They were not working. Then ­another lump occurred next to that one . . . ”

The patient is young, healthy and doesn’t smoke. He has a sore throat and a neck mass that doesn’t respond to antibiotics.

Those in the front lines of ­medical practice, she said, should have in mind the question: Could this patient have head and neck cancer?

Transgene announced Tuesday it is teaming up with Merck KGaA of Darmstadt, Germany, and Pfizer to evaluate the possibilities of the combination of its human papillomavirus (HPV)-positive head and neck cancer vaccine TG40001 with big pharma’s avalumab in a Phase 1/2 study.

The incidence of HPV-related head and neck cancers has increased significantly, with one variation, HPV-16 accounting for 90% of all HPV-related head and neck cancers. HPV-16 is a subset of head and neck squamous cell carcinoma (HNSCC), a group of cancers that can affect the mouth and throat. Global spending on head and neck cancer indications amounted to $1 billion in 2010, according to the companies’ recent estimates.

Current treatments for the disease include surgical resection with radiotherapy or chemo-radiotherapy; the companies say they are exploring better options for advanced and metastatic HPV and HNSCC.

Dive Insight:
The current deal between the big pharma partners and Transgene highlights the industry’s efforts to create combination therapies to treat cancer. Virtually every company in the space has embraced the idea that using multiple modes of attack could be the only way to eventually find cures for the many forms of cancer; companies have been teaming up in hopes of finding that crucial pairing.

In previous clinical trials, TG4001 has demonstrated promising activity in terms of HPV viral clearance and was well tolerated, according to Transgene. TG4001 is one of the few drugs targeting HPV-associated cancers that can be combined with an immune checkpoint inhibitor such as avelumab.

TG4001 is an active immunotherapeutic designed by Transgene to express the coding sequences of the E6 and E7 tumor associate antigens of HPV-16, and the cytokine, L IL-2. Avelumab is an investigational fully human antibody specific for a protein found on tumor cells called PD-L1. It is considered to have a mechanism that may enable an immune system to locate an attack cancer cells. In 2014, Merck KGaA and Pfizer signed a strategic alliance to co-develop and commercialize avelumab.

“The preclinical and clinical data that have been generated with both TG4001 and avelumab individually suggest this combination could potentially demonstrate a synergistic effect, delivering a step up in therapy for HPV- positive HNSCC patients,” said Philippe Archinard, chairman and CEO of Transgene, in a statement.

Christophe Le Tourneau, the principal investigator of the study, said HPV-induced head and neck cancers are now treated with the same regimen as non-HPV-positive HNSCC tumors, and that is not enough. “Their different etiology clearly suggests that differentiated treatment approaches are needed for HPV-positive patients,” he said in a statement. “Targeting two distinct steps in the immune response could deliver improved efficacy for patients who have not responded to or have progressed after a first line of treatment,” added Le Tourneau, who is also head of the Early Phase Program at Institut Curie.

This trial is expected to begin in France, with the first patients expected to be recruited in the beginning of 2017, said Le Tourneau. The companies will seek to recruit patients with recurrent and/or metastatic virus-positive oropharyngeal squamous cell carcinoma that have progressed after definitive local treatment or chemotherapy, and cannot be treated with surgical resection and/or re-irradiation.

A drastic increase in the number of HPV-associated oropharynx cancers, particularly those of the tonsil and base of tongue, has captured the attention of head and neck oncologists worldwide.

In February, at the Multidisciplinary Head and Neck Cancer Symposium in Chandler, Ariz., Maura Gillison, MD, PhD, professor and Jeg Coughlin Chair of Cancer Research at The Ohio State University in Columbus, presented data that showed that the proportion of all head and neck squamous cell cancers that were of the oropharynx — which are most commonly HPV-positive cancers — increased from 18% in 1973 to 32% in 2005.

Maura Gillison, MD, PhD, Jeg Coughlin Chair of Cancer Research at The Ohio State University, said screening for HPV in the head and neck is years behind cervical screening for HPV.

In addition, studies from the United States, Europe, Denmark and Australia indicate that HPV-positive patients have a more than twofold increased cancer survival than HPV-negative patients, according to Gillison.

With the rising incidence of HPV-related oropharynx cancers, it will soon be the predominant type of cancer in the oral or head and neck region, according to Andy Trotti, MD, director of radiation oncology clinical research, H. Lee Moffitt Cancer Center & Research Institute, in Tampa, Fla.

“We should be focusing on HPV-related oropharyngeal cancer because it will dominate the field of head and neck cancers for many years,” he said during an interview with HemOnc Today. “It is certainly an important population for which to continue to conduct research.”

Because HPV-associated oropharyngeal cancer is emerging as a distinct biological entity, the recent rise in incidence will significantly affect treatment, and prevention and screening techniques, essentially reshaping current clinical practice.

Social change driving incidence

In the analysis performed by Gillison and colleagues, trends demonstrated that change in the rates of head and neck cancers was largely due to birth cohort effects, meaning that one of the greatest determinants of risk was the year in which patients were born.

The increased incidence of HPV-related oropharyngeal squamous cell carcinoma started to occur in birth cohorts born after 1935, indicating that people who were aged in their teens and twenties in the 1960s were demonstrating increased incidence, Gillison said.

“Two important and probably related events happened in the 1960s. In 1964, the surgeon general published a report citing smoking as a risk factor for lung cancer, and public health policy began promoting smoking cessation along with encouragement not to start smoking,” she told HemOnc Today.

If you were 40 years old between 2000 and 2005, your risk for having HPV-related cancer is more than someone who was between the age of 40 and 45 years in 1970, according to Gillison. Social changes that occurred among people born after 1935, for example, a reduction in the number of smokers, is consistent with the increasing proportion of oropharyngeal cancers that were HPV-related.

“The rates for HPV-related cancers began to increase and the rates for HPV-unrelated cancers started to decline, consistent with the known decline in tobacco use in the U.S. population,” she said.

Now, most cases of head and neck squamous cell carcinoma in non-smokers are HPV-related; however, oral HPV infection is common and is a cause of oropharyngeal cancer in both smokers and non-smokers, research shows.

In addition to a decrease in tobacco use reducing HPV-unrelated oral cavity cancers, the number of sexual partners may have increased during this time and have helped to increase HPV-related oropharyngeal cancers, according to Gillison.

Determining the cause of the elevated incidence is only a small piece of the puzzle. Screening, establishing who is at risk, and weighing vaccination and treatment options are all relevant issues that must be addressed.

Screening is problematic

A critical area for examination and research is the issue of screening for oral cancers. In contrast to cervical cancer, there is no accepted screening that has been shown to reduce incidence or death from oropharyngeal cancer, according to Gillison.

Not many studies have examined the issue of screening for HPV-unrelated oral cancers, and the few that have, tend to include design flaws.

Gillison said there is a hope that dentists would examine the oral cavity and palpate the lymph nodes in the neck as a front-line screen for oral cancer; however, in her experience, and from her perspective as a scientist, this has never been shown to provide benefit for oral cancer as a whole.

Another caveat with regard to HPV detection is that head and neck HPV screening is about 20 years behind the cervical field.

“Clinicians screening for HPV in the field of gynecology were incredibly fortunate because Pap smear screening was already an accepted cervical cancer screening method before HPV was even identified,” she said. “There was already a treatment algorithm: If there were cytologic abnormalities, patients were referred to the gynecologist, who in turn did a colposcopy and biopsy.”

A similar infrastructure does not exist for oropharyngeal cancer. People with HPV16 oral infection are at a 15-fold higher risk for oropharynx cancer and a 50-fold increased risk for HPV-positive head and neck cancer, yet there is no algorithm for treatment and management of these at-risk individuals, Gillison said.

In 2007, WHO said there was sufficient evidence to conclude that HPV16 was the cause of oropharynx cancer, but with no clinical algorithm already established, progress in this area is much further behind.

Another problematic aspect of HPV-related oropharyngeal cancer screening is that the site where the cancer arises is not accessible to a brush sampling, according to Gillison.

“To try to find this incredibly small lesion in the submucosal area that you cannot see and cannot get access to with a brush, highlights that we need to develop new techniques, new technologies and new approaches,” she said.

The near future consists of establishing the actual rates of infection in the oral cavity and oropharynx, and then screening for early diagnosis, according to Erich Madison Sturgis, MD, MPH, associate professor in the department of head and neck surgery and the department of epidemiology at The University of Texas M.D. Anderson Cancer Center.

“I am not extremely hopeful because the oropharyngeal anatomy makes screening complicated, and these cancers likely begin in small areas within the tonsils and the base of the tongue,” Sturgis told HemOnc Today. “I am hopeful, however, that preventive vaccines will eventually, at a population level, start to prevent these cancers by helping people avoid initial infection by immunity through vaccination earlier in life.”

Much of the currently known information surrounding the issue of HPV-related oral cancers is new, so researchers continue to conduct research in various relevant areas. One key question to answer is who may be at higher risk for HPV-related oropharynx cancers.

Who is at risk?

As mentioned earlier, the number of oral sex partners seems to play a role in the risk for contracting the HPV virus.

In one study published in The New England Journal of Medicine in 2007, findings demonstrated that a high lifetime number of oral sex partners (at least six partners) was associated with an increased risk for oropharyngeal cancer (OR=3.4; 95% CI, 1.3-8.8).

In addition to a higher number of oral sex partners, other still unknown factors may be contributing to risk. This is an area that needs further research, according to Barbara Burtness, MD, chief of head and neck oncology, and professor of medical oncology at Fox Chase Cancer Center in Philadelphia.

The effect of smoking status is another area that needs further research. According to Burtness, smokers with HPV-associated oropharynx cancer have less favorable outcomes.

When discussing the prognosis of HPV-associated cancers, Sturgis said low risk is defined as low or no tobacco exposure and positive HPV status, and intermediate risk is defined as significant tobacco exposure but an HPV-positive tumor, and the highest risk group appears to be the HPV-negative group.

Although HPV-negative cancers are overwhelmingly tobacco-related cancers and tend to have multiple mutations, it appears that HPV-positive cancers, particularly those in patients with low tobacco and alcohol exposure, tend to lack mutations and to have a better prognosis, and this may ultimately help to guide treatment practices, according to Sturgis. Yet, there is still much to learn about HPV-related oropharyngeal cancers on various fronts.

Vaccination a hopeful ally

In HPV-related head and neck cancer, particularly oropharynx cancers, more than 90% of patients who have an HPV-type DNA identified, have type 16, according to Sturgis.

The two current HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), which are approved for cervical cancers, include HPV types 16 and 18; therefore, in theory, they should be protective against the development of infections in the oropharynx and protective at preventing these HPV-associated cancers from occurring.

The presumption is that if there was a population-wide vaccination against HPV, there would be less person-to-person transmission, and this would lead to fewer oropharynx cancers, according to Burtness, who said this theory still needs further research.

There is excitement at the possibility that therapeutic vaccines could be developed, and various groups are investigating this, Burtness added.

“There is reason to think that the vaccines may be helpful; however, when HPV infects the tonsillar tissues, it exerts control in the host cells by making two proteins: E6 and E7; so another potentially exciting therapeutic avenue would be to target those specific viral proteins,” she told HemOnc Today.

Anxiety about protection from the HPV virus is palpable, according to Sturgis. He described the worry that many patients experience about contracting and transmitting HPV infection.

“Many patients are concerned they will put their spouses and/or children at risk in ways such as kissing them; and we need to tone down those worries until we have better data,” he said.

Screening and vaccination are fundamental aspects of current ongoing research, but of equal importance is determining what clinicians should do to treat a population of patients with HPV-related oropharyngeal cancers.

HPV status may influence treatment

With rates of HPV-related cancers escalating, determining the appropriate treatment for these patients is crucial.

During the past 10 years, findings from retrospective studies have shown that patients with HPV-related cancers have a much better prognosis than patients who test negative for HPV. Findings from several retrospective analyses from clinical trials conducted during the past 2 years have come to the same conclusion, according to Gillison: HPV-positive patients have half the risk for death compared with patients negative for HPV.

Therefore, there may be several alternative treatment options, including the possibility of reducing the dose of radiation given to patients after chemotherapy, thereby reducing toxicity.

Comparing HPV-negative and HPV-positive patients may not be enough to determine proper treatment, researchers said. Data between different cohorts of HPV-positive patients also needs to be examined. Smoking, for example, may play a role in patient outcome.

In a prospective Radiation Therapy Oncology Group clinical trial (RTOG 0129), presented by Gillison at the 2009 ASCO Annual Meeting and recently published in The New England Journal of Medicine (see page 53), researchers conducted a subanalysis of the effect of smoking on outcome in uniformly staged and treated HPV-positive and HPV-negative patients while accounting for a number of potential confounders. HPV-positive patients who were never smokers had a 3-year OS of 93% compared with heavy smoking HPV-negative patients who had an OS of 46%.

The study found that smoking was independently associated with OS and PFS. Patients had a 1% increased risk for death and cancer relapse for each additional pack-year of smoking. This risk was evident in both HPV-positive and HPV-negative patients. Gillison said smoking data must be paid attention to, and she encouraged cooperative group research on the topic.

Most of the findings demonstrate improved outcomes for patients with HPV-positive oropharyngeal cancers vs. patients with HPV-negative oropharyngeal cancers, according to the experts interviewed by HemOnc Today.

Dose de-intensification for less toxicity

To date, there is no evidence that HPV-related cancers should be managed differently than HPV-unrelated cancers, but it is a hot topic among clinicians in the field, according to Burtness.

The superior outcomes for HPV-associated oropharynx cancer have suggested the possibility of treatment de-intensification. The use of effective induction chemotherapy may permit definitive treatment with a lower total radiation dose. In theory, this would reduce the severity of late toxic effects of radiation, such as swallowing dysfunction. Such a trial is being conducted by the Eastern Cooperative Oncology Group. Burtness said this is currently pure research question.

“There is still much research that needs to be done before clinicians can safely reduce the dose of radiation administered to HPV-positive patients,” Burtness said.

Currently, she and colleagues in the ECOG are conducting a study of patients with HPV-associated stage III or IV oropharynx cancers to examine the possibility of tailoring therapy to these patients. Patients are assigned to one of two groups: low-dose intensity-modulated radiotherapy 5 days per week for 5 weeks (27 fractions) plus IV cetuximab (Erbitux, ImClone) once weekly for 6 weeks, or standard-dose intensity-modulated radiotherapy 5 days per week for 6 weeks (33 fractions) plus IV cetuximab once weekly for 7 weeks.

If patients have a very good clinical response to chemotherapy, which is likely to happen with HPV-associated cancers, they are eligible to receive a reduced dose of radiation, and hopefully, they would experience less adverse effects, Burtness said.

“Patients who are treated with the full course of radiation for head and neck cancer are now getting 70 Gy, and they are often left with dry mouth, and speech and swallowing difficulty,” she said. “We are hopeful that if these particular cancers are treatment responsive to chemotherapy, we may be able to spare the patient the last 14 Gy of radiation.”

Immunotherapy a viable treatment

Another possible treatment technique that may benefit patients with HPV-related cancers is immunotherapy. One form of immunotherapy uses lymphocytes collected from the patient, and training the cells in the laboratory to recognize in this case a virus that is associated with a tumor and consequently attack it. This approach potentially may be used to treat HPV-related oropharynx cancers, according to Carlos A. Ramos, MD, assistant professor at the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston.

“With some infections that lead to cancer, even though the virus is present in the tumor cells, the proteins shown to the immune system are limited; therefore, they do not drive a very strong immune response,” Ramos told HemOnc Today. “Training the immune system cells, T lymphocytes, may make them respond better to antigens.”

Data from ongoing trials that are taking T lymphocytes from patients and educating them to recognize antigens in patients with the Epstein-Barr virus associated tumors have shown some activity against them, according to Ramos. This adoptive transfer appears to be safe and may have the same effect on the HPV virus associated tumors. Immunotherapy does not cause the usual toxicities associated with chemotherapy, he said.

“There are currently no trials showing whether we can prevent more recurrences with this approach, but the results of trials examining viruses such as Epstein-Barr are good so far, in both patients who have no evidence of disease and in those who still have disease,” he said.

Even patients with active disease who have not responded to other therapies have responded to this therapy, Ramos said. He and colleagues are working toward compiling preclinical data to study the possibility of using immunotherapy to treat patients with HPV-related cancers.

Journey is just beginning

Much of what is known about risk, screening, prevention and treatment of HPV-related oropharynx cancers is in the early stages of discovery and much is still theoretical, according to Sturgis.

“As far as we can tell, these infections are transmitted sexually; the hope is that as we have better vaccines for prevention of cervical dysplasia, the downstream effect will help prevent other HPV-related cancers, such as anal cancers and penile cancers and oropharyngeal cancers,” he said.

Several recent studies examining new therapies that may reduce the intensity of traditional treatments while maintaining survival rates would have a major effect on the field, according to Sturgis.

Gillison said the rise in the number of cases of HPV-related cancers is changing the patient population considered to be at risk, and more research is vital.

“The most important thing for clinicians to do is be aware that trials are being developed and strongly encourage their patients to participate,” she said. Christen Cona

*This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

Patients with head and neck cancer who underwent PET/CT–guided surveillance achieved similar survival outcomes as those who underwent planned neck dissections, according to the results of a prospective, randomized controlled trial. However, surveillance led to fewer surgical operations and complications and appeared more cost-effective than neck dissection, results showed.

Patients with head and neck cancer frequently undergo invasive surgery following treatment to remove remaining cancer cells, according to study background.

“After treatment, remaining cancer cells play something akin to hide and seek,” Hisham Mehanna, MBChB, PhD, FRCS, chair of head and neck surgery at University of Birmingham and director of the Institute of Head and Neck Studies and Education, said in a press release. “Our study shows that we can hunt them down, find them and remove them effectively.”

Mehanna and colleagues sought to define the role of image-guided surveillance compared with planned neck dissection for the management of patients with advanced, nodal head and neck squamous cell carcinoma previously treated with primary chemoradiotherapy. The analysis included data from 564 patients (mean age, 58 years; 82% men) who researchers randomly assigned to PET/CT–guided surveillance (n = 282) performed 12 weeks after the end of treatment or planned neck dissection (n = 282).

Oropharyngeal cancer served as the most common cancer subtype (84%). Seventy-five percent of patients had HPV-16–positive disease. Patients assigned surveillance only underwent neck dissection if their PET/CT scans showed incomplete or equivocal response to chemoradiotherapy.

The trial was designed to assess noninferiority of PET/CT–guided surveillance. OS served as a coprimary endpoint. Median follow-up was 36 months, with 92% of patients (n = 520) followed for at least 2 years. Ninety-six percent of patients assigned surveillance underwent PET/CT per protocol at 12 weeks. Fifty-four patients in the surveillance arm underwent neck dissections compared with 221 patients in the planned surgery arm. The surgical complication rate was similar in both cohorts (42% vs. 38%). Overall, 122 patients had died at the time of reporting (surveillance, n = 60; neck dissection, n = 62).

HPV–16 status did not have a significant effect on OS. Survival appeared comparable between the planned surgery and surveillance groups among patients with p16–positive (HR = 0.74; 95% CI, 0.4-1.37) and p16–negative tumors (HR = 0.98; 95% CI, 0.58-1.66). Both arms had similar rates of 2-year locoregional control (91.9% vs. 91.4%).

More patients assigned neck dissection experienced an adverse event (169 vs. 113). Patients in the surveillance arm had better quality of life scores at 6 months (P = .03); however, this difference became nonsignificant by 12 months. Surveillance appeared more cost-effective than neck dissection, with a per-person cost savings of $2,190.

“Patient outcomes, and avoiding unnecessary surgery, are the main goals of this study,” Mehanna said. “But there is a cost saving to be made, too. … Carry that [savings] across the tens of thousands of cases each year across the world and you see a significant saving that can be redistributed into other therapies.” – by Cameron Kelsall

Source:N Engl J Med. 2016;doi:10.1056/NEJMoa1514493.

Disclosure:
The National Institute for Health Research Health Technology Assessment Program funded this study. Please see the full study for a list of the researchers’ relevant financial disclosures.

Seven HPV types in Gardasil 9 (HPV 16, 18, 31, 33, 45, 52, and 58) cause approximately 90% to 95% of HPV-related anal cancers, 90% of cervical cancers, and 80% of high-grade cervical lesions worldwide.These 7 types also cause the majority of HPV-related vulvar and vaginal cancers. Gardasil 9 includes the greatest number of HPV (Human Papillomavirus) types of any available HPV vaccine.

Gardasil 9 was previously approved for use in girls and young women aged 9 to 26 years for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV 16, 18, 31, 33, 45, 52, and 58, precancerous or dysplastic lesions caused by HPV 6, 11, 16, 18, 31, 22, 45, 52, and 58, and genital warts caused by HPV types 6 and 11. As for use in male patients, the vaccine was previously approved for use in boys aged 9 to 15 years for the prevention of anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58, precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.

With the newest approval, Gardasil 9 is now also indicated for use in males aged 16 to 26 years for the prevention of these diseases. According to the CDC, HPV vaccination rates are unacceptably low compared to rates for other adolescent vaccines, and vaccination coverage in males is especially low in males. The approval of the expanded age indication in male patients was based on results from a clinical trial program for Gardasil 9 that was designed to build upon the safety and efficacy established in clinical trials with Gardasil [Human Papillomavirus Quadrivalent (types 6, 11, 16, and 18) Vaccine, Recombinant].

“Any health plans that have not yet made a decision regarding coverage for Gardasil 9 for males 16-26 can do so now that that the vaccine is indicated in this population,” according to a company statement from Merck. “Most managed care plans have already made decisions to cover the cost of Gardasil 9, including for males 16 through 26 years of age, making the number of plans covering Gardasil 9 similar to the number covering the cost of Gardasil. The approval of Gardasil 9 for males 16 through 26 years of age is a milestone in the planned transition from Gardasil to Gardasil 9, as both products are now approved for the same populations.”

The most common adverse reactions associated with the use of Gardasil 9 in males aged 16 to 26 years included injection-site pain, swelling, and erythema. Not all vulvar, vaginal and anal cancers are caused by HPV; Gardasil 9 only protects against those cancers caused by HPV 16, 18, 31, 33, 45, 52, and 58. Gardasil 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of Gardasil 9 or Gardasil.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

The presence of HPV16 DNA is common at diagnosis of HPV-related oropharyngeal carcinoma (HPV-OPC) but rare after treatment. HPV-OPC has a favorable prognosis; however, 10% to 25% of patients experience disease progression, usually within 2 years of treatment.

Patients who have HPV 16 DNA in their saliva following treatment of their oropharyngeal cancer are more likely to have their cancer recur, and a prospective cohort study published in JAMA Oncology has shown that a simple mouth rinse can be used to detect it.

Gypsyamber D’Souza

Gypsyamber D’Souza, PhD, Johns Hopkins Bloomberg School of Public Health, and fellow researchers monitored 124 patients with newly diagnosed oropharyngeal cancer from 2009 through 2013. They collected oral rinse and gargle samples using 10 mL of mouthwash at the time of diagnosis as well as after treatment 9, 12, 18, and 24 months later.

HPV16 DNA was detected in 67 out of 124 of the participants testing positive. Of the 67 patients who had HPV16 DNA in their saliva at the time of diagnosis, five patients (7%) were found to still have traces of HPV16 in their oral rinses following treatment.

All five patients developed a local recurrence of oropharyngeal cancer, three of whom died from the disease.

“It’s a very small number so we have to be somewhat cautious,” said D’Souza, an associate professor in the Department of Epidemiology at the Bloomberg School and a member of the Sidney Kimmel Comprehensive Cancer Center, in a statement. However, “The fact that all of the patients with persistent HPV16 DNA in their rinses after treatment later had recurrence meant that this may have the potential to become an effective prognostic tool.”

Local drugmakers – big and small – struck a deal to try to develop a vaccine to prevent a form of cervical, head and neck cancer.

MedImmune, which is the biologics and research division with AstraZeneca, said Monday it will collaborate with Inovio Pharmaceuticals to develop an early stage cancer vaccine designed to treat human pappilomavirus.

AstraZeneca will pay Inovio $27.5 million upfront. If the compound reaches development and commercial milestones, Inovio could get up to $700 million, along with “double-digit tiered royalties” on product sales. However, sales are a long way off because the compound is only in phase I and phase II of what is normally a three-phase clinical trial process.

AstraZeneca is moving its headquarters from London to Cambridge in the United Kingdom, and has operations in Wilmington and Fort Washington. The MedImmune division is headquartered in Gaithersburg, Md.

Inovio is based in Blue Bell and its basic scientific premise is to use DNA to develop vaccines. unlike most current vaccines.

The companies have worked together before. The compound at the heart of the latest deal is called INO-3112. The early clinical trials are examining cervical and head and neck camcers and the compound tries to generate “killer T-cell responses that are able to destroy HPV 16- and 18- driven tumors. These HPV types are responsible for more than 70 per cent of cervical pre-cancers and cancers, ” according to the statement.

A new blood and saliva test that looks for traces of the human papillomavirus (HPV) can predict whether some people with oral cancers will have their cancer come back, early research suggests.

It helps to know as soon as possible that cancer has returned, because tumors that are caught early are easier to treat.

In the study, the researchers analyzed blood and saliva samples from 93 people with head and neck cancers; about 80 percent of these patients had cancers that tested positive for HPV. All of their cancers had previously been treated with surgery, radiation or chemotherapy.

The researchers looked for fragments of DNA from HPV-16, a strain of the virus that is strongly linked with head and neck cancer. The virus may be found in cancer cells that linger in the body after treatment, the researchers said.

Among people with HPV-positive tumors, the new test identified 70 percent of those whose cancer returned within three years, the researchers said.

“Until now, there has been no reliable biological way to identify which patients are at higher risk for recurrence, so these tests should greatly help [to] do so,” study researcher Dr. Joseph Califano, professor of otolaryngology at Johns Hopkins School of Medicine, said in a statement.

Patients with head and neck cancer typically visit the doctor every one to three months during the first year after their diagnoses to check for cancer recurrence. But new tumors in the tonsils, throat and base of the tongue can be difficult to spot, and are often not detected early, the researchers said.

Still, more research is needed to confirm the findings, Califano said. Because HPV infection is common, the test may identify HPV infections that are not related to the cancer. “We can’t be sure our test results are cancer-specific, and not due to other forms of HPV infection or exposure,” Califano said.

The researchers are now looking for additional genetic markers that would increase the accuracy of their test.

Note:
The study is published today in the journal JAMA Otolaryngology–Head & Neck Surgery.

While the incidence of smoking-related oral squamous cell carcinoma has decreased in many parts of the world, cases of human papilloma virus (HPV) positive oropharyngeal cancer (OPSCC) have greatly increased. Otolaryngologists are finding that the majority of their patients are male and a lot younger in age than their counterparts. This “new” head and neck cancer patient differs in several ways from the “traditional” head and neck cancer patients who were older, had significant tobacco and alcohol exposure, and potential tumours throughout the upper aerodigestive tract. The significance of this global trend suggests that more attention needs to be paid to the phenomena here in the Middle East.

Dr Marilene Wang, Professor, Chief of Otolaryngology, UCLA Department of Head and Neck Surgery, will be discussing the increasing incidence of young cancer patients who are non-smokers, but happen to be HPV positive and how these cases should be managed in the Middle East at the 11th Middle East Update in Otolaryngology Conference & Exhibition – Head and Neck Surgery (ME-OTO) from the 20-22 April 2014 at the Madinat Jumeirah Arena, Dubai, UAE.

According to Dr Wang, “Currently, the most common head and neck cancer patients are younger, primarily male, and have no or relatively minimal exposures to tobacco and alcohol. Yet, they often have histories of notable increased sexual encounters. Although HPV positive OPSCC demonstrates an alarming increasing incidence, this is balanced by a significant response to treatment regardless of advanced stage.

“Cases of OPSCC associated with HPV have increased 225% in the US from 1988-2004. HPV infection is ubiquitous, as up to 85% of adults may have an HPV infection at some point from any of the over 120 subtypes. Only a small percentage of these subtypes develop malignancy and these are primarily related to the HPV-16 subtype. There is also an increased risk of OPSSC in husbands of women with cervical cancer and in situ cancer.”

The majority of epidemiological studies on HPV positive OPSCC have been done in the Western hemisphere, where there is a documented rise in the incidence of both HPV infection and HPV positive OPSCC. The impact of HPV in other parts of the world is less clear.

“A recent study from Turkey did document an increase in the incidence of HPV positive OPSCC between 1996 and 2011, from 33% to 70% (Dural et al. Asian Pac J Cancer Prev. 2013; 14(10):6065-8). Further studies will need to be done to determine the incidence of HPV-positive OPCC in the Middle East,” says Dr Wang.
“Vaccination against HPV is recommended for adolescents and young adults, boys and girls, ages 9 -25, ideally prior to onset of sexual activity. This commonly utilized vaccine provides protection against the 4 strains of HPV most associated with cervical and OPSCC, including HPV-16. However, there is no evidence to support efficacy of the vaccine to treat HPV-related cancers,” concludes Dr Wang.